ABSTRACT
Anthracyclines are highly potent anti-cancer drugs, but their clinical use is limited by severe cardiotoxic side effects. The impact of anthracycline-induced cardiotoxicity (AIC) on left ventricular (LV) microarchitecture and diffusion properties remains unknown. This study sought to characterize AIC by cardiovascular magnetic resonance diffusion tensor imaging (DTI). Mice were treated with Doxorubicin (DOX; n = 16) for induction of AIC or saline as corresponding control (n = 15). Cardiac function was assessed via echocardiography at the end of the study period. Whole hearts (n = 8 per group) were scanned ex vivo by high-resolution DTI at 7 T. Results were correlated with histopathology and mass spectrometry imaging. Mice with AIC demonstrated systolic dysfunction (LVEF 52 ± 3% vs. 43 ± 6%, P < 0.001), impaired global longitudinal strain (-19.6 ± 2.0% vs. -16.6 ± 3.0%, P < 0.01), and cardiac atrophy (LV mass index [mg/mm], 4.3 ± 0.1 vs. 3.6 ± 0.2, P < 0.01). Regional sheetlet angles were significantly lower in AIC, whereas helix angle and relative helicity remained unchanged. In AIC, fractional anisotropy was increased (0.12 ± 0.01 vs. 0.14 ± 0.02, P < 0.05). DOX-treated mice displayed higher planar and less spherical anisotropy (CPlanar 0.07 ± 0.01 vs. 0.09 ± 0.01, P < 0.01; CSpherical 0.89 ± 0.01 vs. 0.87 ± 0.02, P < 0.05). CPlanar and CSpherical yielded good discriminatory power to distinguish between mice with and without AIC (c-index 0.91 and 0.84, respectively, P for both < 0.05). AIC is associated with regional changes in sheetlet angle but no major abnormalities of global LV microarchitecture. The geometric shape of the diffusion tensor is altered in AIC. DTI may provide a new tool for myocardial characterization in patients with AIC, which warrants future clinical studies to evaluate its diagnostic utility.
ABSTRACT
Background: Obesity exerts multiple deleterious effects on the heart that may ultimately lead to cardiac failure. This study sought to characterize myocardial microstructure and function in an experimental model of obesity-related cardiac dysfunction. Methods: Male C57BL/6N mice were fed either a high-fat diet (HFD; 60 kcal% fat, n = 12) or standard control diet (9 kcal% fat, n = 10) for 15 weeks. At the end of the study period, cardiac function was assessed by ultra-high frequency echocardiography, and hearts were processed for further analyses. The three-dimensional myocardial microstructure was examined ex vivo at a spatial resolution of 100 × 100 × 100 µm3 by diffusion tensor magnetic resonance imaging (DT-MRI) at 7T. Myocardial deformation, diffusion metrics and fiber tract geometry were analyzed with respect to the different myocardial layers (subendocardium/subepicardium) and segments (base/mid-cavity/apex). Results were correlated with blood sample analyses, histopathology, and gene expression data. Results: HFD feeding induced significantly increased body weight combined with a pronounced accumulation of visceral fat (body weight 42.3 ± 5.7 vs. 31.5 ± 2.2 g, body weight change 73.7 ± 14.8 vs. 31.1 ± 6.6%, both P < 0.001). Obese mice showed signs of diastolic dysfunction, whereas left-ventricular ejection fraction and fractional shortening remained unchanged (E/e' 41.6 ± 16.6 vs. 24.8 ± 6.0, P < 0.01; isovolumic relaxation time 19 ± 4 vs. 14 ± 4 ms, P < 0.05). Additionally, global longitudinal strain was reduced in the HFD group (-15.1 ± 3.0 vs. -20.0 ± 4.6%, P = 0.01), which was mainly driven by an impairment in basal segments. However, histopathology and gene expression analyses revealed no myocardial fibrosis or differences in cardiomyocyte morphology. Mean diffusivity and eigenvalues of the diffusion tensor were lower in the basal subepicardium of obese mice as assessed by DT-MRI (P < 0.05). The three-dimensional fiber tract arrangement of the left ventricle (LV) remained preserved. Conclusion: Fifteen weeks of high-fat diet induced alterations in myocardial diffusion properties in mice, whereas no remodeling of the three-dimensional myofiber arrangement of the LV was observed. Obese mice showed reduced longitudinal strain and lower mean diffusivity predominantly in the left-ventricular base, and further investigation into the significance of this regional pattern is required.
